Drg-mdm2-6 for use as a novel mouse double minute 2 (mdm2) inhibitor

ABSTRACT

The invention relates to compound shown with formula (I) or a pharmaceutically acceptable derivative thereof for use as a novel inhibitor of MDM2 activity.

TECHNICAL BACKGROUND

The p53 is an important gene that protects the cell cycle and acts as atumor suppressor. It plays important roles in the regulation of cellularfunctions, DNA repair, neurodegenerative diseases, aging, ischemia,apoptosis and cell cycle arrest. Many of these p53 activities play arole in suppression of tumor by preventing oncogenic damage, repairingor eliminating oncogenic progressive cells. Loss of p53 function isassociated with development of cancer in various organs. In the case ofmetabolic stress and increase of oncogenes, p53 levels are alsoincreasing. Optimal increases in p53 levels are vital. However,excessive or insufficient p53 level is a clear sign of malfunctioning ofthe gene. Former causes apoptosis whereas latter leads to tumorformation. The natural negative regulator of p53 is the Mouse DoubleMinute 2 (MDM2), an endogenous p53 inhibitor. The MDM2 gene is aproto-oncogene that negatively regulates the transcriptional activationof p53 by p53 ubiquitination. This arrangement is very important toprotect low levels of p53, maintaining normal cell cycle progression andcell survival. Thus, the most common p53 suppression mechanism involvethe MDM2.

The p53 is an unstable protein with a half-life of 5-30 minutes innormal cells without stress. It is monoubiquitinated continuously byMDM2 to be broken down by proteasomes in the nucleus and cytoplasm. MDM2is expressed in the nucleus under normal cellular conditions but can bedisplaced in the cytoplasm and mediated to disintegration by proteasomesof some targets such as p53. In case of cellular stress, the p53 pathwayis activated and leads to tumor cell inhibition by inhibiting theproliferation of cells with oncogenic potential. The p53 pathway ismainly inactivated due to overexpression of endogenous negativeregulators (especially MDM2). More than 17% of tumors present MDM2 geneamplification leading to poor prognosis and treatment failure inchemotherapeutics.

The significance of p53-MDM2 interaction was demonstrated by in vivoexperiments. MDM2 amplification was observed in human sarcomas. Variousapproaches have been used to antagonize the p53 inhibition effect of theMDM2. These methods involve development of MDM2 antagonists whichinhibit p53-MDM2 interactions. Thus, direct inhibition of MDM2 may causeinhibitory and therapeutic activity because it can inhibit bothp53-dependent and p53-independent functions of MDM2. MDM2 levelsincrease in ovarian cancers, while it is very low in benign ovariantumors and normal ovaries. The overexpressed MDM2 is directly bound tothe N-terminal domain of p53 and inhibits with one of the followingmechanisms: (i) Stimulate the ubiquitin-dependent p53 degradation in thenuclear and cytoplasmic 26S proteasomes by acting as E3 ubiquitinligase; (ii) reducing the transcriptional ability of p53 by promotingthe transport of p53 from the nucleus to the cytoplasm; (iii)interacting strongly with p53, reducing its ability to bind to DNA,which makes p53 transcriptionally dysfunctional. The irregularity of thep53-MDM2 pathway, including p53 mutations and deletions and/or MDM2amplification and overexpression, is the most frequently observedmolecular change in various human cancers. p53-MDM2 balance disruptioncan lead to malignant transformation of normal cells and may also affectchemosensitivity of tumor cells. MDM2 overexpression leads to thesuppression of apoptotic function of p53 and hence uncontrolledproliferation of cancer cells.

MDM2 protein consists of four functional independent domains includingN-terminal domain to which p53 is linked (nuclear localization sequence(NLS), the nuclear export sequence (NES), the Box-1 domain) (aa 19-102);central acidic domain (aa 223-274); zinc finger domain (aa 305-322) andRING finger domain which is critical for E3 ubiquitin ligase activity(aa 438-478).

STATE OF THE ART

The inhibition of p53-MDM2 interactions with small molecules has beenhighly suggested and numerous MDM2 inhibitors have been discovered, inrecent years. The structural features of the p53-MDM2 complex leads fordesigning of small molecules that mimic key residues to prevent p53-MDM2interactions. Nutlin compounds that are capable of inducing apoptosis incancer cells and disrupting p53-MDM2 interaction and restoring p53functions are the most well-known MDM2 antagonists. Nutlins arewell-known compounds for their antitumor profiles in wild-type p53cells. Selective nutlins for inhibition of p53-MDM2 interaction are cisimidazoline class of small molecules. The Nutlin derivative MI-219(contains oxindole ring) induces apoptosis in cancer cells in vitro andin vivo by inhibiting the p53-MDM2 interactions. MI-219 has been shownto selectively inhibit the growth of wild-type p53-containing lungcancer cells by cell cycle arrest in the G1 or G2 phase. The analogue ofMI-219 and nutlin-3a, an oxindole derivative (MI-319), is a syntheticsmall molecule that binds the MDM2 protein with 500-fold high bindingaffinity from a natural p53 peptide. Studies have shown that MI-319, incombination with the chemotherapeutic drug cisplatin, suppresses cellcycle growth synergistically and induces apoptosis in pancreatic cancercell lines. 7-nitro-5-deazaflavin and deazaflavin-5 are powerful MDM2 E3ligase inhibitors that perform the autoubiquitination of MDM2. Becauseof the medical importance of the oxindole and indole compounds,derivatives of these compounds having cytotoxic activity against cancercell lines have been reported. Spirotetrahydrothiopyran oxindolescaffold was formed as an inhibitor of p53-MDM2 and showed a good potentas MDM2 inhibitor and antitumor activity. The antitumor activity ofspirocyclic oxindole skeleton against human lung cancer cell A549, humanliver cancer cell BEL7402 and human colon cancer cell HCT-8 wasinvestigated. Indole derivatives have been shown to be potent and havehigh therapeutic activity against different cancer types. Some of thecurrently used FDA approved chemotherapeutics contain indole ring whoseantitumor activities are evaluated at the clinical stage.

Even though there are certain molecules that are interfering with thep53 and MDM2 interaction there is still need for novel drugs with betterpharmacokinetic profiles that can serve as MDM2 inhibitors such that p53can show beneficial effect against uncontrolled tumor growth.

The inventors have found that a new compound shown with formula I actsas an inhibitor of p53-MDM2 interaction.

The compound shown with formula I according to present invention is thusa representative of a novel compound that is suitable for use in severaldisorders where an interaction of p53-MDM2 pathway plays a role. Suchdiseases can for example be proliferative diseases such as cancer.Therefore, present invention not only relates to novel compounds shownwith formula I but also to use of said compounds for treatment ofproliferative diseases such as cancer.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compound shown with formula I, which isDRG-MDM2-6, or a pharmaceutically acceptable derivative thereof.

Unless specified otherwise, the terms “compound of the presentinvention” or “compound of invention” or “compound of formula I” or“compound shown with formula I” are used interchangeable and refer tocompounds of formula I and salts thereof, hydrates or solvates of thecompound of formula I or its salts, all stereoisomers (diastereomers andenantiomers), tautomers, isotopically labeled compounds (includingdeuterium substitutions), or its forms that form under physiologicalconditions of the human body, as well as inherently formed moieties(e.g., polymorphs, solvates and/or hydrates).

In other words, the term “pharmaceutically acceptable derivativethereof” refers to hydrates, solvates, prodrugs, all stereoisomers,salts, esters, tautomers, isotopically labeled derivatives or forms ofcompound of formula I that form under physiological conditions of thehuman body (for example, carboxylate anion form of compound of formulaI, named as Formula Ia).

Several embodiments of the invention are described herein. It must beconsidered that each specified embodiment can be combined with otherspecified features to provide further embodiments. The terms used in thesingular will also include plural and vice versa.

As disclosed herein the term “enantiomers” mean a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Compound of formula Ihas a chiral center. In a preferred embodiment of the invention compoundof formula I is in the form of a 1:1 racemic mixture of R and Senantiomers. The compound of formula I can also be in pure R form or inpure S form or a mixture thereof in any ratio.

The present invention includes all possible isomers including racematesand optically pure forms of compound of formula I. Said forms can beprepared by using conventional techniques known in the art such as byuse of chiral reagents or other methods.

As disclosed herein the term “salts” mean acid addition of base additionsalts of the compound of invention. In particular the salts include “thepharmaceutically acceptable salts” which refer to salts that retain thebiological effectiveness and effectiveness of the compound of inventionwhile not having any biologically or otherwise unwanted properties suchas toxicity or causing any kind of formulation difficulties.

Pharmaceutically acceptable acid addition salts can be formed withorganic acids and/or inorganic acids. Acid addition salts of thecompound according to present invention can be selected from a groupcomprising; acetate, aspartate, benzoate, besylate,bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate,ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate,lauryl sulfate, malate, maleate, malonate, mandelate, mesylate,methylsulphate, naphthoate, napsylate, nicotinate, nitrate,octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate,succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetatesalts.

Pharmaceutically acceptable base addition salts can be formed withorganic bases and/or inorganic bases. Bases appropriate for preparationof base addition salts of the compound of the invention can be selectedfrom sodium hydroxide, sodium carbonate, sodium bicarbonate, calciumhydroxide, calcium carbonate, calcium bicarbonate, magnesium hydroxide,magnesium carbonate, magnesium bicarbonate, potassium hydroxide,potassium carbonate, potassium bicarbonate and the like.

As disclosed herein the term “isotopically labeled compounds” refers tocompounds of formula I wherein one or more atoms are replaced with anatom having selected atomic mass or mass number. Such replacements canbe made with for example; ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S,³⁶Cl, ¹²⁵I. Such isotopically labaled variants of compound of theinvention can be used for detection or imaging techniques known in theart or for radioactive treatment of patients.

p53 refers to the human protein itself as described by Matlashewski etal. in EMBO J. 3, 3257-62 (1984) or related family members. MDM2(especially when mentioned as MDM2 or variants thereof) generally refersto all genes and/or proteins encoded thereof with the names MDM2, Mdm2,HDM2, Hdm2, or a variant thereof.

In another aspect present invention relates to pharmaceuticalcompositions comprising compound of formula I, DRG-MDM2-6, or apharmaceutically acceptable derivative thereof and at least onepharmaceutically acceptable excipient.

In a preferred embodiment of the invention, the pharmaceuticallyacceptable excipient can be selected from a group comprising; solvents,antioxidants, preservatives (e.g. antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, sats,preservatives, stabilizers, binders, disintegrants, lubricants,sweetening agents, flavoring agents and combinations thereof. Particularexamples of each group are disclosed in Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990 and incorporated hereinby reference.

The pharmaceutical compositions comprising compound of formula I can beformulated for different routes of administration. In an embodiment ofthe invention, pharmaceutical compositions comprising compound offormula I can be formulated for oral administration, parenteraladministration, topical administration or rectal administration.

In a preferred embodiment of the invention, pharmaceutical compositionsof the invention for oral administration can be in the form of tablets,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsion, hard or soft capsules, or syrups or elixirs.

In a preferred embodiment of the invention, pharmaceutical compositionsof the invention for parenteral administration can be in the form ofisotonic solutions or suspensions or in to form of lyophilized powdersuitable for reconstitution prior to administration. Said pharmaceuticalcompositions of the invention for parenteral administration can be forintramuscular, intravenous, subcutaneous, intraperitoneal, intratrachealadministration.

In a preferred embodiment of the invention, pharmaceutical compositionsof the invention for topical administration can be in the form ofaqueous solutions, suspensions, ointments, pastes, lotions, transdermalpatches, gels, creams, or sprayable formulations such as aerosols. Suchtopical administration covers administration through skin, eye or nose(i.e. intranasal administration). Thus, pharmaceutical compositions ofthe invention can be in the form of dry powders, solutions or aerosolsfor administration through pressurized containers, pump, spray, atomizeror nebulizer with or without a suitable propellant.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

In another aspect the invention relates to compound of formula I,DRG-MDM2-6, or a pharmaceutically acceptable derivative thereof for usein treatment of a disorder where p53-MDM2 interaction plays a role.

In a preferred embodiment, the invention, relates to compound of formulaI, DRG-MDM2-6, or a pharmaceutically acceptable derivative thereof foruse in treatment of a disorder mediated by the activity (includingnormal activity or especially over activity) of MDM2.

In a preferred embodiment, a disorder mediated by the activity of MDM2is a proliferative disease such as cancer.

In an embodiment of the invention, cancer includes benign or malignanttumors, a soft tissue sarcoma or a sarcoma (e.g. liposarcoma,rhabdomyosarcoma) or bone cancer (e.g. osteosarcomas), a carcinoma (e.g.such as of the brain, kidney, liver, adrenal gland, bladder, breast,gastric, ovary, colon, rectum, prostate, pancreas, lung, vagina orthyroid), a glioblastoma, meningioma, glioma, mesothelioma, a multiplemyeloma, a gastrointestinal cancer (especially colon carcinoma orcolorectal adenoma), a tumor of the head and neck, a melanoma, aprostate hyperplasia, a neoplasia, a neoplasia of epithelial character,a leukemia such as acute myeloid leukemia or B-cell chronic lymphocyticleukemia, a lymphoma (such as of B- or T-cell origin) and metastases inother organs.

In another aspect the invention relates to the use of a compound offormula I or salt thereof as defined herein, for the manufacture of amedicament for the treatment of a disorder or a disease in a subjectmediated by the activity of MDM2.

In another aspect, the invention relates to the use of a compound offormula I or a salt thereof as defined herein to induce cell cycledeceleration or preferably arrest and/or apoptosis in cells containingp53 or variants thereof that are still functional, for sensitizing cellsto one or more additional pharmaceutically active agents, such asinducers of apoptosis and/or of cell cycle deceleration or arrest.

In another aspect, the invention relates to combinations comprisingcompound of formula I and one or more additional active agent selectedfrom a group comprising; anti-proliferative agents, immunomodulatoryagents, antiviral agents, antimicrobial agents, anti-infective agents,anti-inflammatory agents, anesthetic agents, antiemetics or combinationsthereof where appropriate. In a preferred embodiment additional activeagent is one or more anti-proliferative agent.

In an embodiment of the invention, anti-proliferative active agent canbe one or more of the agents selected from the group comprising but notlimited to; alkylating agents, anthracyclines, taxanes (cytoskeletaldisruptors), epothilones, histone deacetylase inhibitors, inhibitors oftopoisomerase I, inhibitors of topoisomerase II, kinase inhibitors,tyrosine kinase inhibitors, nucleotide analogs and precursor analogs,peptide antibiotics, platinum based agents, retinoids, vincaalkaloidsand derivatives or other agents.

Alkylating agents can be selected from a group comprising but notlimited to; bendamustine, cyclophosphamide, mechlorethamine,chlorambucil, melphalan, dacarbazine, nitrosoureas, streptozotocin,temozolomide, trabectedin.

Anthracyclines can be selected from a group comprising but not limitedto; daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,valrubicin.

Taxanes (cytoskeletal disruptors) can be selected from a groupcomprising but not limited to; paclitaxel, docetaxel, abraxane,taxotere, cabazitaxel,

Epothilones can be selected from a group comprising but not limited to;epothilone A, epothilone B, epothilone C, epothilone D, epothilone E,epothilone F or pharmaceutically acceptable derivatives thereof such asixabepilone.

Histone deacetylase inhibitors can be selected from a group comprisingbut not limited to; belinostat, panobinostat, valproate, vorinostat,romidepsin.

Inhibitors of topoisomerase I can be selected from a group comprisingbut not limited to; irinotecan, topotecan.

Inhibitors of topoisomerase II can be selected from a group comprisingbut not limited to; etoposide, teniposide, tafluposide.

Kinase inhibitors can be selected from a group comprising but notlimited to; bortezomib, erlotinib, gefitinib, imatinib, vemurafenib,vismodegib.

Tyrosine kinase inhibitors can be selected from a group comprising, butnot limited to, afatinib, axitinib, bosutinib, cobimetinib, crizotinib,dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib,osimertinib, pazopanib, ruxolitinib, sunitinib, vandetanib.

Nucleotide analogs and precursor analogs can be selected from a groupcomprising but not limited to; azacitidine, azathioprine, cladribine,clofarabine, capecitabine, cytarabine, doxifluridine, decitabine,floxuridine, fludarabine, fluorouracil (5-FU), fluorouracil,gemcitabine, hydroxyurea, mercaptupurine, methotrexate, nelarabine,pentostatin, tioguanine, trifluridine, tipiracil.

Peptide antibiotics can be selected from a group comprising but notlimited to; bleomycin, actinomycin.

Platinum based agents can be selected from a group comprising but notlimited to; carboplatin, cisplatin, oxaliplatin.

Retinoids can be selected from a group comprising but not limited to;tretinoin, alitretionoin, bexarotene, isotretinoin, tamibarotene.

Vincaalkaloids and derivatives can be selected from a group comprisingbut not limited to; vinblastine, vincristine, vindestine, vinflunine,vinorelbine.

Other agents can be selected from a group comprising but not limited to;methotrexate, pemetrexed, pralatrexed, raltitrexed, etoposideteniposide, abiraterone, bicalutamide, cyproterone, degarelix,exemestane, fulvestrant, goserelin, histrelin, leuprolide, mifepristone,triptorelin, lenalidomide, pomalidomide, thalidomide, everolimus,temsirolimus, anagrelide, ceritinib, dabrafenib, idelalisib, ibrutinib,palbociclib, vemurafenib, bleomycin, dactinomycin, eribulin,estramustine, ixabepilone, mitomycin, procarbazine, alectinib,fluxymesterone, iobenguane, imiguimod, interferon, ixazomib, lanreotide,lentinan, octreotide , omacetaxine, tegafur, gimerazil, oteracil,uracil, combretastatin.

In an embodiment of the invention, such combinations can be in a formwherein compound of formula I and one or more therapeutically activeagents, preferably anti-proliferative agents are formulated together.

In another embodiment of the invention, compound of formula I and one ormore therapeutically active agents, preferably anti-proliferative agentsare formulated separately but they are administered to a patient in needthereof simultaneously or sequentially.

Comprising in the context of the present specification is intended tomeaning including.

Where technically appropriate, embodiments of the invention may becombined.

Embodiments are described herein as comprising certainfeatures/elements. The disclosure also extends to separate embodimentsconsisting or consisting essentially of said features/elements.

Technical references such as patents and applications are incorporatedherein by reference.

Any embodiments specifically and explicitly recited herein may form thebasis of a disclaimer either alone or in combination with one or morefurther embodiments.

The invention will now be described with reference to the followingexamples, which are merely illustrative and should not in any way beconstrued as limiting the scope of the present invention.

EXAMPLES Example 1: Cell Culture Experiments

HCT 116 colon cancer and MDA-MB231 breast cancer cell lines are used incell culture experiments.

Cells were treated with high-glucose DMEM medium (Biosera) supplementedwith 10% FBS (Gibco) and 1× penicillin/streptomycin (Multicell). Theassay was designed to contain 10,000 cells for each well of 24-well cellculture plates before being treated with inhibitors.

Compound of formula I was dissolved with DMSO as 20 mM stock. 24 hourslater, the the solution was diluted in DMEM with 10% FBS and finalconcentration of vehicle DMSO was 0.5% at maximum. Therefore, thevehicle group included 0.5% DMSO concentration in experiments. Intensivecultivation of cells causes a decrease in proliferation capacity.Therefore, the confluency did not exceed 60%.

The MTT cell viability assay was used to detect values of half-maximalinhibitory concentration (IC₅₀). Different concentrations of compound offormula I ranging between 10⁻⁹ to 10⁻⁴ M were tested on MDA-MB231 celllines with single dose of treatment. 570 nm absorbance values wererecorded and IC₅₀ values were calculated by dose response-inhibitioncurves and nonlinear regression analysis on Graphpad Prism 8 software.IC₅₀ value of compound of formula I was determined to be 13 μm (FIG. 1).

Example 2: Cell Proliferation Inhibition Analysis

For proliferation inhibition analysis, cells were seeded in 24 wellplates at 1×10⁴ cells/well cells overnight without drug treatment.During the cell proliferation experiments, we performed five days oftreatment in each cell line and repeated the experiments three times tocheck each experiment. No significant difference in cell viability wasobserved after the third day. Therefore, cells with different drugconcentrations were treated for two days. After 48 hours, MTT wasapplied to the cells and incubated at at 37° C. for 4 hours, formazanwas solubilized with DMSO (Sigma-Aldrich, St. Louis, USA) and absorbancewas measured at 570 nm.

MTT cell proliferation assay results are shown in FIG. 2 . Moleculeconcentration was 100 μM, the lower concentrations were not shown.Vehicle represents the groups treated with only % 0.5 DMSO and Untreatedrepresents no molecule treated group. Molecule responses were evaluatedby cell viability which is obtained by spectrophotometric analysis ofcells upon MTT treatment at 12 h, 24 h, 48 h and 72 h. Molecule groupsshowed statistically significant difference compared to vehicle anduntreated groups. Statistical significance in graphs was determined bycomparing each treatment group with DMSO control using ANOVA testing andsignificance is considered as p<0.001 (FIG. 2 ).

1. A compound shown with formula I which is DRG-MDM2-6, or apharmaceutically acceptable derivative thereof.


2. A compound according to claim 1 wherein pharmaceutically acceptablederivative of formula I can be its hydrates, solvates, prodrugs, allstereoisomers, salts, esters, tautomers, isotopically labeledderivatives or forms of compound of formula I that form underphysiological conditions of the human body.
 3. A compound according toclaim 2 wherein pharmaceutically acceptable derivative of compound offormula I is shown with formula Ia.


4. A compound according to claims 1-3 wherein the compound is in theform of a 1:1 racemic mixture of R and S enantiomers.
 5. A compoundaccording to claims 1-4 for use in treatment of a disorder wherep53-MDM2 interaction plays a role.
 6. A compound for use as claimed inclaim 5 wherein the disorder is a proliferative disease.
 7. A compoundfor use as claimed in claim 6 wherein proliferative disease is cancer.8. A compound for use as claimed in claim 7 wherein cancer is benign ormalignant tumors, a soft tissue sarcoma or a sarcoma (e.g. liposarcoma,rhabdomyosarcoma) or bone cancer (e.g. osteosarcomas), a carcinoma (e.g.such as of the brain, kidney, liver, adrenal gland, bladder, breast,gastric, ovary, colon, rectum, prostate, pancreas, lung, vagina orthyroid), a glioblastoma, meningioma, glioma, mesothelioma, a multiplemyeloma, a gastrointestinal cancer (especially colon carcinoma orcolorectal adenoma), a tumor of the head and neck, a melanoma, aprostate hyperplasia, a neoplasia, a neoplasia of epithelial character,a leukemia such as acute myeloid leukemia or B-cell chronic lymphocyticleukemia, a lymphoma (such as of B- or T-cell origin) and metastases inother organs
 9. A compound according to claims 1-4 for use incombination with one or more additional pharmaceutically active agent.10. A compound for use as claimed in claim 9 wherein additionalpharmaceutically active agent is selected from a group comprisinganti-proliferative agents, immunomodulatory agents, antiviral agents,antimicrobial agents, anti-infective agents, anesthetic agents,antiemetics or combinations thereof.
 11. A compound for use as claimedin claim 10 wherein antiproliferative agents are selected from a groupcomprising alkylating agents, anthracyclines, taxanes (cytoskeletaldisruptors), epothilones, histone deacetylase inhibitors, inhibitors oftopoisomerase I, inhibitors of topoisomerase II, kinase inhibitors,tyrosine kinase inhibitors, nucleotide analogs and precursor analogs,peptide antibiotics, platinum based agents, retinoids, vincaalkaloidsand derivatives or other agents.
 12. A pharmaceutical compositioncomprising a compound according to claims 1-4 and at least onepharmaceutically acceptable excipient.
 13. A pharmaceutical compositionscomprising a compound according to claims 1-4 and one or more additionalpharmaceutically active agent selected from a group comprisinganti-proliferative agents, immunomodulatory agents, antiviral agents,antimicrobial agents, anti-infective agents, anesthetic agents,antiemetics or combinations thereof.